Treatment of low pressure glaucoma and ischemic retinal degeneration

ABSTRACT

The invention relates to a method for increasing blood flow to the retina and choroid in subjects with decreased retinal or choroidal blood flow. The method involves the topical administration of metoclopramide and is useful for the treatment of low pressure glaucoma and ischemic retinal degeneration.

TECHNICAL FIELD

The present invention relates generally to a method for the improvementof blood flow to the retina and choroid in order to halt or reverse thecourse of visual deterioration. More specifically, it relates to thetreatment of ischemic retinal degeneration and low pressure glaucoma.

BACKGROUND OF THE INVENTION

Glaucoma is a leading cause of blindness affecting approximately 3million people in the United States. About one-third of the patientpopulation afflicted with glaucoma suffers from what is known as lowtension glaucoma. R. Weinreb, Eye Research Seminar, Research to PreventBlindness, (1990) p. 14-15. This type of glaucoma is not associated withelevated intraocular pressure (IOP). However, antiglaucoma agents aregenerally designed to lower the IOP in order to improve the ocular bloodflow, particularly at the choroid, retina and lamina cribosa of theoptic nerve. Such antiglaucoma agents are ineffective for the treatmentof low tension glaucoma, as the IOP of these patients is already low.Therefore most low tension glaucoma patients undergo a filteringoperation instead of being treated with antiglaucoma drugs. Chandler etal. Glaucoma, Lea & Febiger, Philadelphia, 111-115 (1965).

Ischemic retinal degeneration, or degeneration of the central part ofthe retina, is the second leading cause of blindness among people of allages. It causes at least some loss of vision in 10 million people overthe age of 50. Lierman, Building a Healthy America, Mary Ann LiebertInc., New York 115-119 (987). This ischemic retinal degeneration iscaused by various diseases, including diabetic retinopathy, glaucoma,sickle cell retinopathy, vascular abnormalities, obstructive arterialand venous retinopathies, venous capillary insufficiency, hypertensiveretinopathy, inflammation, tumors, retinal detachment, etc. U.S. Dept ofHealth & Human Services, Vision Research, Report of Retinal and ChoroidDiseases Panel, NIH Publication #83-2471 (1983). LeVail et al., RetinalDegeneration, Experimental and Clinical Studies, Alan R. Liss Inc., NewYork (1985).

The retina is supplied with oxygen and nutrients by two vascularsystems, one within the retina itself (central retinal artery) and onein the choroid (posterior ciliary artery). Interruption or impairment ofeither system leads to degeneration of the retina and ultimately to lossof vision. There are many diseases and conditions that affect retinalcirculation and nutritional supply. Early improvement in blood flow ornutrient supply to the retina in some of these diseases and throughoutthe time course of others might be the key to slowing vision loss oreliminating it altogether.

Various dopamine antagonists have been shown to lower IOP. U.S. Pat.Nos. 4,565,821 and 4,772,616 describe the use of butypherones (i.e.haloperidol, trifluperidol and moperone) and domperidone to lowerintraocular pressure. U.S. Pat. No. 4,521,414 describes the use of the Risomer of timolol as an anti-hypertensive agent for the eye. The use ofthe dopamine antagonists haloperidol, moperone, trifluperidol,clofluperol, pipamperone and lemperone in the treatment of ocularhypertension and glaucoma is also described. Chiou, Ophthal. Res.16:129-134 (1984).

Although the foregoing references describe the use of dopamineantagonists to decrease IOP, Chiou et al., J. Ocular Pharmacy, 528-292(1989) found that some dopamine antagonists increase IOP as well. Chiouet al. hypothesized that dopamine antagonists may decrease ciliary bloodflow at post-synaptic sites in order to lower the IOP and improve ocularblood flow.

It has also been shown that all dopamine antagonists do not act onocular blood flow uniformly. For example, haloperidol, moperone andtrifluperidol were found to reduce the blood flow to the retina andchoroid. Chiou et al., Ophthal. Res. 18:265-269 (1986), and Yan et al.Ophthal. Res. 19:45-48 (1987). Although domperidone was found toincrease the retinal blood flow, it also caused eye irritation.

DISCLOSURE OF THE INVENTION

The present invention is based on the finding that certain dopamineantagonists increase ocular blood flow without eye irritation. Thus,these drugs provide a convenient means for treating or preventing visualdeterioration associated with decreased blood flow.

Accordingly, the present invention relates to a method to increase bloodflow to the retina or choroid in a subject with decreased retinal andchoroidal blood flow. The method involves administering atherapeutically effective amount of metoclopramide to the subject.

In one aspect, the invention is drawn to the use of metoclopramide toincrease blood flow to the retina for the treatment of low pressureglaucoma.

In a second aspect, the invention is drawn to the use of metoclopramideto increase blood flow to the retina for the prevention of ischemicretinal degeneration.

In another embodiment, the invention relates to a method to prevent ortreat visual deterioration associated with decreased choroidal orretinal blood flow. The method comprises administering a therapeuticallyeffective amount of metoclopramide to a subject with decreased bloodflow.

In a further embodiment, the invention relates to an ocular deliverydevice comprising metoclopramide.

In yet another embodiment, the invention relates to a pharmaceuticalcomposition comprising metoclopramide in admixture with apharmaceutically acceptable vehicle. The composition is useful for thetreatment or prevention of visual deterioration associated with diseasesor conditions that reduce blood flow to the retina and choroid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is applicable to the treatment or prevention ofvisual deterioration associated with diseases or conditions thatdecrease retinal or choroidal blood flow. Metoclopramide has been shownto increase the blood flow at the retina and choroid. Low tensionglaucoma and ischemic retinal degeneration appear to be associated withdecreased ocular blood flow. Accordingly, the use of metoclopramideaffords a method for treating these disorders. Additionally,metoclopramide does not produce local irritation to the eyes.

Metoclopramide is a commercially available substance with the followingstructure: ##STR1##

Definitions

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

"Decreased blood flow" as used herein refers to choroidal or retinalblood flow that is below normal human retinal blood flow. Normal bloodflow has been reported in the range of 8.1 to 18.5 μl/min.

"Treatment" as used herein refers to the reduction or elimination ofvisual deterioration resulting from decreased blood flow to the retinaand choroid (therapy).

"Prevention" refers to the treatment of patients with decreased retinaland/or choroidal blood flow to avoid visual deterioration (prophylaxis).

"Pharmaceutically active substance " as used herein refers to asubstance that has been shown to be useful in the treatment of decreasedocular blood flow. In the present invention, pharmaceutically activesubstances include metoclopramide.

"Pharmaceutical composition" refers to a composition containing thepharmaceutically active substance. The composition may also contain apharmaceutically acceptable vehicle.

"Therapeutically effective amount" as used herein refers to an amount ofa pharmaceutically active substance useful in the prevention ortreatment of visual deterioration.

"Ischemic retinal degeneration" is the degeneration of the retina andoccurs as a result of the impairment or interruption of the supply ofoxygen or other nutrients to the retina via the central retinal arteryor to the choroid via the posterior ciliary artery. Such impairment orinterruption may result from various diseases and conditions such asdiabetic retinopathy, glaucoma, sickle cell retinopathy, vascularabnormalities, obstructive arterial and venous retinopathies, venouscapillary insufficiency, hypertensive retinopathy, inflammation, tumors,and retinal detachment.

Administration

The administration of metoclopramide can be via any of the acceptedmodes of administration of pharmaceutical compositions. These methodsinclude topical administration of solutions, suspension ointments orgels, parenteral injection, or oral administration.

Depending on the intended mode of administration, the compositions maybe in the form of solid, semi-solid or liquid dosage forms, such as forexample, tablets, pills, capsules, powders, liquids, suspensions, or thelike, preferably in unit dosage forms suitable for single administrationof precise dosages. The compositions will include a conventionalpharmaceutical vehicle and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, etc. Theamount of active compound administered will, of course, be dependent onthe subject being treated, the manner of administration and the judgmentof the prescribing physician.

The conventional pharmaceutical vehicle should be compatible with thepharmaceutically active substance of the pharmaceutical composition.Suitable vehicles for ocular use are, for example, sterile isotonicsolutions such as isotonic sodium chloride or boric acid solutions.These vehicles typically contain sodium chloride or boric acid,respectively, as well as benzalkonium chloride and sterile distilled orpurified water. Also useful is phosphate buffered saline (PBS), pH 7.4.Other suitable vehicular constituents include phenylmercuric nitrate,sodium sulfate, sodium sulfite, disodium phosphate and monosodiumphosphate.

The compositions may also contain auxiliary substances, i.e.antimicrobial agents such as chlorobutanol, parabens or organicmercurial compounds; pH adjusting agents such as sodium hydroxide,hydrochloric acid or sulfuric acid; and viscosity increasing agents suchas methylcellulose. One of ordinary skill in the art will easily findsubstitutes for the above auxiliary substances. The final compositionshould be sterile, essentially free of foreign particles, and have a pHthat allows for optimum drug stability. Generally, pH values in therange of 5-8 will find use with the subject composition. Preferably, thepH will be as close to the pH of tear fluid, i.e. 7.4 as possible.

Typically, the compositions of the subject invention are prepared assolutions, suspensions, ointments, gels, or ocular delivery devices suchas drug-impregnated solid carriers that are inserted into the eye. Ifsuch a carrier is used, the above-mentioned vehicles are unnecessary. Avariety of polymers can be used to formulate ophthalmic drug carriers.Saettone, M. F., et al., J. Pharm. Pharmocol (1984) 36:229, and Park, K.et al., in Recent Advances in Drug Delivery Systems, Anderson et al.,eds., Plenum Press (1984) 163-183, describe such polymers, thedisclosures of which are incorporated herein by reference in theirentirety. Drug release is generally effected via dissolution orbioerosion of the polymer, osmosis, or combinations thereof. The deviceshould be formulated to release the drug at a rate that does notsignificantly disrupt the tonicity of tear fluid.

More specifically, several matrix-type delivery systems can be used withthe subject invention. These systems are described in detail in Ueno etal., "Ocular Pharmacology of Drug Release Devices", in Controlled DrugDelivery, Bruck, ed., vol. II, Chap 4 CRC Press Inc. (1983), thedisclosure of which is incorporated herein by reference in its entirety.Such systems include hydrophilic soft contact lenses impregnated orsoaked with the desired drug, as well as biodegradable or solubledevices that need not be removed after placement in the eye. Thesesoluble ocular inserts can be composed of any degradable substance thatcan be tolerated by the eye and that is compatible with the drug to beadministered. Such substances include but are not limited to poly(vinylalcohol), polymers and copolymers of polyacrylamide, ethylacrylate, andvinylpyrrolidone, as well as cross-linked polypeptides orpolysaccharides, such as chitin.

Capsule-type delivery systems will also find use with the instantinvention. These systems, described in Ueno et al., supra, utilizepolymer membranes to control the release of the drug in question. Thesedevices are particularly useful for the delivery of hydrophilic drugs.Hydrophobic drugs can be administered via a silicone rubber device suchas described in Ueno et al., supra.

Ophthalmic ointments will include a base, generally composed of whitepetrolatum and mineral oil, often with anhydrous lanolin.Polyethylene-mineral oil gel is also satisfactory, as are othersubstances that are non-irritating to the eye, permit diffusion of thedrug into the ocular fluid, and retain activity of the medicament for areasonable period of time under storage conditions. If suspensions areused, the particle sizes therein should be less than 10 μm to minimizeeye irritation. Furthermore, if solutions or suspensions are used, theamount delivered to the patient should not exceed 50 μl, preferably 25μl or less, to avoid excessive spillage from the eye.

For solid compositions, conventional nontoxic solids including, forexample, pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like may be used. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc. an active compound as defined above and optionalpharmaceutical adjuvants in a vehicle, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,etc. Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art, for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975.

For topical administration, i.e. application of solutions, suspensions,ointments, gels, etc. directly to the eye, the composition may contain0.01-10.0% active ingredient, preferably 0.1-1.0%. An effective amountfor the purposes of preventing or treating visual deterioration isusually in the range of 0.01-0.1 mg/kg. The compound may be administeredevery 4-8 hours. Preferably, the compound is administered every 6 hours.

The subject compounds can also be administered by implantation of aslow-release or sustained-release system, such that a constant level ofdosage is maintained. For a review of these sustained release systemssee Ueno, et al., "Ocular Pharmacology of Drug Release Devices", inControlled Drug Delivery, Bruck, ed., vol. II, Chap 4, CRC Press Inc.(1983). The pharmaceutically effective amount of metoclopramide to haltor reverse the course of visual deterioration is usually in the range of0.1-2.0 mg/day. A new implant should be inserted every 3-10 days.Preferably, a new implant is inserted every 5-7 days.

For oral administration, a pharmaceutically acceptable nontoxiccomposition is formed by the incorporation of any of the normallyemployed vehicles described above. Such compositions take the form ofsolutions, suspensions, tablets, pills, capsules, powders,sustained-release formulations and the like. Such compositions maycontain 1-95% active ingredient, preferably 1-10%. An effective amountfor the purposes of preventing or treating visual deterioration isusually in the range of 0.01-0.1 mg/kg. The compound may be administeredevery 4-8 hours. Preferably, the compound is administered every 6 hours.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable vehicles are, for example,water, saline, dextrose, glycerol, ethanol or the like. In addition, ifdesired, the pharmaceutical compositions to be administered may alsocontain minor amounts of nontoxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents and the like, such as, forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleate,etc. An effective amount for the purposes of preventing or treatingvisual deterioration is usually in the range of 0.01-0.1 mg/kg. Thecompound is administered as described above with regard to oraladministration.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples which follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLES Example 1 Preparation of an Animal Model for Ocular Blood FlowA. Materials

L-Timolol was obtained from Merck, Sharp and Dohme (West Point, Pa.).Metoclopramide was purchased commercially from A. H. Robins Inc.(Richmond, Va.). Colored microspheres were purchased from E-Z Trac (LosAngeles, Calif.). The colored microspheres were diluted with salinecontaining 0.01% v/v of Tween 80 to keep the microspheres from stickingtogether. One million microspheres were injected at each time point.

B. Methods

New Zealand albino rabbits, weight 2.5-3.0 kg, were anesthetized with 35mg/kg ketamine and 5 mg/kg xylazine intramuscularly. Half of the initialdose was given at one hour intervals afterward to maintain adequateanesthesia. The left ventricle of the heart was cannulated through theright carotid artery for microsphere injection, and the femoral arterywas cannulated for blood sampling. The blood flow was measured withcolored microspheres at -30 min for normal ocular blood flow and at 0min for ocular blood flow with an IOP of 40 mm Hg. Metoclopramideeyedrops were instilled topically at time 0 min, and the blood flow wasdetermined at 30, 60, 120, and 180 minutes thereafter. At each injectionof microspheres, blood samples were taken from the femoral artery forexactly 60 seconds immediately after the injection of the microspheresas a reference.

After the last injection of the microspheres and the collection of bloodsamples, the animals were euthanized. The eyes were enucleated anddissected into the retina, choroid, iris and ciliary body. The tissuesamples were weighed The blood sample was collected in a heparinizedtube, and the volume was recorded.

The details of sample processing and microsphere counting were providedby E-Z Trac. Tissue samples were added to Tissue/Blood Digest Reagent Iin the microfuge tubes, sealed and heated at 95° C. for 15 minutes. Theywere vigorously vortexed for 15-30 seconds, then reheated and revortexeduntil the tissue samples were all dissolved. Tissue/Blood Digest ReagentII was then added while the samples were hot, and the tubes were cappedand vortexed. The tubes were then centrifuged to settle the microspheresto the bottom of the tubes. The supernatant was aspirated, and thepellet was resuspended in the precise volume of Microsphere Countingreagent with vortex. If the sediment aggregated, it was dispersed withan ultrasonic bath. The number of various colored microspheres were thencounted with a hemocytometer.

Hemolysis Reagent was added to the blood sample, vortexed, andcentrifuged in a low speed centrifuge for 30 minutes. The supernatantwas aspirated, and the Tissue/Blood Digest Reagent I was added. Theprocedure was the same as described above to process tissue samples, andthe colored microspheres were counted with a hemocytometer.

C. Results

The blood flow of each tissue at a certain time point was calculatedfrom the following equation:

    Q.sub.m =(C.sub.m ×Qr)/Cr

where Q_(m) is the blood flow of a tissue in terms of μl/min/mg. C_(m)is the microsphere count per mg of tissue, Q_(r) is the flow rate ofblood sample in terms of μl/min, and C_(r) is the microsphere count inthe referenced blood sample.

All data were expressed as mean±standard error of the mean. Student'st-test was used to analyze the significance between the two means. Theblood flow was considered significantly different from the controlvalues at p<0.05.

The ocular blood flow of normotensive animals is presented in Table 1.When the IOP was raised to 40 mm Hg, the blood flow was reduced toapproximately 1/3 of the normal blood flow. The reduced blood flowremained stable during the entire experimental period of 3 hours. Thisis an animal model with reduced ocular blood flow and is useful fortesting the effects of drugs to improve the ocular blood flow.

Example 2 The Effects of Metoclopramide on Ocular Blood Flow

25 μl of 0.5% metoclopramide eyedrops were instilled into the eyes ofthe animal models described in Example 1. The blood flow in all oculartissues (iris, ciliary body, retina and choroid) increased significantlyand markedly at 30, 60, 120 and 180 min. (Table 2). At 180 minutes afterdrug instillation, the blood flow in all eye tissues reduced to the 30min. level (Table 2).

Example 3

The Effects of L-Timolol on Ocular Blood Flow

25 μl of 0.5% timolol was instilled into the eyes of the animal modelsprepared in Example 1. The blood flow in the choroid was reducedsignificantly after drug instillation. The blood flow recovered tocontrol levels at 60 min and then all increased significantly at 120 and180 min (Table 3). These results indicate that timolol produced biphasicactions on the ocular blood flow by reducing it initially and thenincreasing it.

Example 4 Eye Irritation

50 μl of 1% metoclopramide was used to test for eye irritation in NewZealand white rabbit eyes using the standard procedure of the DraizeTest. J. Draize et al., J. Pharmacol. Exp. Ther., 82:377-390 (1944).Eyedrops were instilled in the eyes, and the responses of the eyes wereexamined with a slit lamp biomicroscope. Eye irritation was eitherabsent or insignificant.

Modifications of the above described modes for carrying out theinvention that are obvious to persons of skill in the art to which theinvention pertains are intended to be within the scope of the invention.

                                      TABLE 1                                     __________________________________________________________________________    Effect of Ocular Hypertension at IOP of 40 mmHg on Ocular Blood Flow                        Blood Flow (μl/min/mg tissue)                                       Normotensive                                                                         Time After Exertion of IOP at 40 mmHg                                  Eyes   0 min  30 min 60 min 120 min                                                                              180 min                             Tissues                                                                              (N = 5)                                                                              (N = 9 (N = 5)                                                                              (N = 5)                                                                              (N = 5)                                                                              (N = 4)                             __________________________________________________________________________    Iris   .sup. 1.83 ± 0.33.sup.a                                                           0.86 ± 0.25                                                                       0.83 ± 0.24                                                                       0.76 ± 0.23                                                                       0.74 ± 0.26                                                                       0.60 ± 0.05                      Ciliary Body                                                                         1.88 ± 0.26                                                                       0.69 ± 0.26                                                                       0.58 ± 0.20                                                                       0.65 ± 0.19                                                                       0.66 ± 0.19                                                                       0.63 ± 0.08                      Retina  0.21 ± 0.023                                                                     0.068 ± 0.009                                                                     0.057 ± 0.007                                                                     0.065 ± 0.005                                                                     0.057 ± 0.006                                                                     0.059 ± 0.005                    Choroid                                                                              13.25 ± 0.81                                                                      4.30 ± 0.84                                                                       3.87 ± 0.73                                                                       3.65 ± 0.78                                                                       3.52 ± 0.76                                                                       3.05 ± 0.27                      __________________________________________________________________________     .sup. a Mean ± SEM                                                    

                                      TABLE 2                                     __________________________________________________________________________    Effect of 25 μl of 0.5% Metoclopramide on Ocular Blood Flow of Rabbit      Eyes                                                                                        Blood Flow (μl/min/mg tissue)                                              Time After Drug Instillation with IOP of 40 mmHg                       Normotensive                                                                         0 min                                                           Tissues                                                                              Eyes   (control)                                                                            30 min  60 min  120 min 180 min                          __________________________________________________________________________    Iris   .sup. 1.82 ± 0.13.sup.a                                                            0.47 ± 0.080                                                                     0.78 ± 0.11.sup.b                                                                  1.48 ± 0.35.sup.b                                                                  1.09 ± 0.11.sup.b                                                                  0.77 ± 0.06.sup.b             Ciliary Body                                                                         2.38 ± 0.12                                                                        0.60 ± 0.077                                                                     0.97 ± 0.77.sup.b                                                                  1.87 ± 0.34.sup.b                                                                  1.52 ± 0.09.sup.b                                                                  0.81 ± 0.09.sup.b             Retina  0.24 ± 0.013                                                                     0.067 ± 0.004                                                                     0.083 ± 0.007.sup.b                                                                 0.14 ± 0.022.sup.b                                                                 0.13 ± 0.020.sup.b                                                                0.092 ± 0.008.sup.b           Choroid                                                                              13.79 ± 0.75                                                                      3.44 ± 0.33                                                                       6.44 ± 1.43.sup.b                                                                  9.76 ± 2.26.sup.b                                                                  8.65 ± 1.14.sup.b                                                                  5.78 ± 0.50.sup.b             __________________________________________________________________________     .sup.a Mean ± SEM of M = 4 for all except N = 8 for control                .sup.b Statistically different from controls at time 0 min               

                                      TABLE 3                                     __________________________________________________________________________    Effects of 25 μl of 0.5% Timolol on Ocular Blood Flow of Rabbit Eyes                     Blood Flow (μl/min/mg tissue)                                              Time after Drug Instillation with IOP of 40 mmHg                       Normotensive                                                                         0 min                                                                  Eyes   (control)                                                                            30 min 60 min 120 min 180 min                            Tissues                                                                              (N = 5)                                                                              (N = 9)                                                                              (N = 5)                                                                              (N = 5)                                                                              (N = 5) (N = 4)                            __________________________________________________________________________    Iris   .sup. 1.33 ± 0.14.sup.a                                                            0.32 ± 0.038                                                                      0.25 ± 0.036                                                                     0.60 ± 0.10                                                                       1.06 ± 0.15.sup.b                                                                  1.96 ± 0.32.sup.b               Ciliary Body                                                                         1.71 ± 0.23                                                                       0.35 ± 0.057                                                                       0.31 ± 0.072                                                                     0.82 ± 0.21                                                                       1.40 ± 0.18.sup.b                                                                  2.19 ± 0.26.sup.b               Retina  0.22 ± 0.017                                                                     0.058 ± 0.006                                                                     0.055 ± 0.006                                                                     0.079 ± 0.011                                                                      0.20 ± 0.015.sup.b                                                                 0.18 ± 0.017.sup.b             Choroid                                                                              13.15 ± 1.10                                                                      3.50 ± 0.55                                                                       .sup. 1.61 ± 0.20.sup.b                                                           3.73 ± 1.15                                                                       7.79 ± 1.82.sup.b                                                                  10.18 ± 0.82.sup.b              __________________________________________________________________________                                               1                                   .sup.a Mean ± SEM                                                          .sup.b Statistically different from controls at time 0 min.              

I claim:
 1. A method to increase blood flow to the retina or choroidwhich method comprises administering a therapeutically effective amountof metoclopramide to a subject having decreased retinal or choroidalblood flow.
 2. The method of claim 1 wherein the decreased retinal orchoroidal blood flow is due to low pressure glaucoma.
 3. The method ofclaim 1 wherein the decreased retinal or choroidal blood flow is due toischemic retinal degeneration.
 4. The method of claim 3 wherein theischemic retinal degeneration is caused by a disease selected from thegroup consisting of diabetic retinopathy, glaucoma, sickle cellretinopathy, vascular abnormalities, obstructive arterial and venousretinopathies, venous capillary insufficiency, hypertensive retinopathy,inflammation, tumors, and retinal detachment.
 5. The method of claim 1wherein the metoclopramide is administered topically.
 6. The method ofclaim 1 wherein the metoclopramide is administered parenterally.
 7. Themethod of claim 1 wherein the metoclopramide is administered orally. 8.The method of claim 5 wherein topical administration is accomplishedthrough the use of an ocular delivery device.
 9. A method for thetreatment or prevention of visual deterioration associated withdecreased retinal or choroidal blood flow which method comprisesadministering a therapeutically effective amount of metoclopramide to asubject having said decreased retinal or choroidal blood flow.
 10. Themethod of claim 9 wherein the decreased retinal or choroidal blood flowis due to low pressure glaucoma.
 11. The method of claim 9 wherein thedecreased retinal or choroidal blood flow is due to ischemic retinaldegeneration.
 12. The method of claim 11 wherein the ischemic retinaldegeneration is caused by a disease selected from the group consistingof diabetic retinopathy, glaucoma, sickle cell retinopathy, vascularabnormalities, obstructive arterial and venous retinopathies, venouscapillary insufficiency, hypertensive retinopathy, inflammation, tumors,and retinal detachment.
 13. The method of claim 9 wherein themetoclopramide is administered topically.
 14. The method of claim 9wherein the metoclopramide is administered parenterally.
 15. The methodof claim 9 wherein the metoclopramide is administered orally.
 16. Themethod of claim 13 wherein topical administration is accomplishedthrough the use of an ocular delivery device.